Network Pharmacology Combined with Metabolomics Approach to Investigate the Toxicity Mechanism of Paclobutrazol.

Paclobutrazol (PBZ) is a commonly used plant growth regulator (PGR) with good antibacterial activity. It has widespread applications in agricultural production. However, there is limited research reported on the potential risks of human health resulting from PBZ residues. In this study, using Sprague-Dawley rats, we carried out a systematic study on the hepatotoxicity and nephrotoxicity of PBZ in different doses (0.2, 0.5, and 1.0 g/kg). The metabolic profiles and network pharmacology were combined to construct a PBZ-endogenous substances-gene-hepatorenal diseases network to elucidate the underlying mechanism of PBZ's hepatorenal toxicity. At first, metabolomics analysis was done to investigate the metabolites and the related metabolic pathways associated with PBZ. Secondly, the network pharmacology approach was used in further exploration of the toxic targets. Additionally, molecular docking was carried out to investigate the interactions between PBZ and potential targets. The results indicated that PBZ showed obvious toxicity towards the liver and kidney of rats. The metabolomics analysis showed that PBZ mainly affected 4 metabolic pathways, including tryptophan metabolism, arachidonic acid metabolism, linoleic acid metabolism, and purine metabolism. Network pharmacology and molecular docking revealed that CYP1A2, CYP2A6, CYP2E1, MAOA, PLA2G2A, PTGS1, and XDH were critical targets for PBZ hepatorenal toxicity. This preliminary study revealed PBZ's hepatorenal toxicity and provided a theoretical basis for the rational and safe use of PBZ. Furthermore, it provided possible intervention targets for further research on how to avoid or reduce the damage caused by pesticides to the human body.